Positron emission tomography (PET) imaging using Pittsburgh Compound-B (PiB) provides a regional map of amyloid pathology in living subjects and can assist clinical diagnosis of Alzheimer's disease (AD). Understanding the relationship between PiB PET retention patterns in vivo and the underlying pathological burden responsible for PiB retention is necessary to validate PiB as a biomarker in AD. Previous in vitro studies of PiB binding to synthetic p-amyloid (AP) peptide and autopsy brain tissues from AD subjects indicated that PiB PET retention likely reflects PiB binding to AB aggregates in plaques and cerebral vasculature. This idea is supported by our recent clinical-pathological study of AD. However the degree to which PiB PET signal is reflective of neuropathological changes in cognitively normal, MCI, and AD subjects, as well as the AB burden required for positive PiB PET signal in vivo remains to be determined. Furthermore, the degree to which regional synapse loss (the best structural correlate of AD dementia) is reflected by PiB PET retention patterns, and how this is influenced by cerebral vascular pathology (a significant contributor to the development of AD) is currently unknown. With increasing numbers of PiB PET imaged subjects coming to autopsy, we can now address these important issues. We propose to gain insight into these questions in three ways. First, we will characterize PiB's binding substrates in postmortem brain tissues from PiB PET scanned subjects, to determine the type and threshold level of AD pathology which is necessary to produce a positive PiB PET signal in vivo. We will do this in autopsy brain tissues from subjects with different clinical diagnoses, imaged in the previous and current PPG (Projects 4 and 5) at the University of Pittsburgh as well as in other collaborating PiB-PET imaging centers. In the second part of this proposal, we will perform postmortem assessment of synaptic markers and correlate them with region-matched PiB PET and FDG PET levels recorded antemortem (Projects 4 and 5). The third part of this proposal will investigate the extent to which vascular lesions, determined both postmortem and in vivo (Projects 4 and 5), influence the patterns of regional synapse changes and AB plaque load in the same subjects. These autopsy studies will complement clinical imaging and neuropsychological analyses in Projects 4 and 5; while providing greater insight into the AB and vascular pathology burden that influences PiB PET signal, they will secure a unique source of tissues to be utilized in this and future studies of neuropathological correlates of PiB PET imaging.